Summary. Emerging pathogens are global public health threats, with low to middle income countries in Central America having disproportionately high risks for transmission due to large population centers, areas of extreme poverty, and tropical climates. In Belize and El Salvador, more than 6.7 million people are at risk, with 2.3 million living in poverty. Vector-borne, respiratory, and enteric pathogens are of high concern in these vulnerable populations. Outbreaks of dengue virus (DENV) have occurred in this region since the 1970's, and the first autochthonous cases of chikungunya virus (CHIKV) and Zika virus (ZIKV) were reported in 2014 and 2015, respectively. With Aedes aegypti mosquito populations established throughout the region and lack of resources for vector surveillance and control, transmission of these pathogens will continue to be sustained. Autochthonous transmission of parasitic and bacterial vector-borne diseases also occur; however, the true incidence and prevalence of these infections are not known. In deeply impoverished communities that lack public health infrastructure, general health can be poor and malnutrition prevalent, leading to a higher risk of adverse outcomes from respiratory and enteric pathogens. Outbreaks can overwhelm public health systems and severely strain the current diagnostic and case management capacities at the local level. Collectively, endemic and emerging pathogens continue to impact Central America. Considering 1.3 million tourists visit Belize each year alone, the risk of introduction to the US is high. To combat these disease threats, we have convened a strong, multi-disciplinary international team to create an acute febrile illness (AFI) surveillance network to detect and diagnose vector-borne, respiratory, and enteric pathogens within sentinel hospitals in two high-risk areas of Belize (Belize City) and El Salvador (Sonsonate). These sentinel sites are based in tertiary-care hospitals where Baylor College of Medicine (BCM) has current, ongoing projects. The total population served by these hospitals is approximately 829,000. This AFI sentinel surveillance system will work in tandem with vector and animal reservoir surveillance to create a One Health approach to detecting and combating disease threats. We will leverage the academic strengths of US institutions with world-renowned expertise in tropical medicine, entomology, veterinary public health, and informatics: BCM, Texas A&M, University of South Carolina, and Johns Hopkins University. We will collaboratively expand our clinical, education, and research missions, working in tandem with stakeholders from the respective Ministries of Health, local universities, hospital networks, CDC, PAHO, and other US- and Central America-based partners. This collaborative network will provide a preeminent resource to Central America for capacity building, training, applied research, diagnostics, and integrated real-time surveillance for emerging pathogens. Our overall goal is to maximize the ability to understand, detect, and respond to infectious disease threats in a high-risk region. Our One Health-integrated surveillance system based in Central America will strengthen our regional defenses against disease threats.